Aldosterone and myocardial fibrosis in heart failure

Cardiac fibroblasts are known to have high affinity corticoid receptors for aldosterone and account for the accumulation of collagen within the inters titium of the rat myocardium in acquired and genetic hypertension, This int erstitial fibrosis is an important determinant of pathologic hypertrophy in chronic heart failure. To examine the relationship between aldosterone and myocardial fibrosis, co llagen volume fraction of the left and right ventricles were analyzed by vi deodensitometry of sirius red stained tissue in the following rat models: 2 kidney/1 clip model of renovascular hypertension; continuous aldosterone a dministration via osmotic minipumps (0.75 mu g/hour s. c.), or in each mode l of primary and secondary hyperaldosteronism with concomitant treatment wi th either low (20 mg/kg/day) or high doses (200 mg/kg/day) of s. c. spirono lactone for 8 weeks as well as in age matched controls. Systolic arterial p ressure and left ventricular weight normalized to body weight were each inc reased with either model of experimental hypertension and were normalized w ith high-dose spironolactone treatment. Myocardial fibrosis induced by chro nic aldosterone administration was comparable to renovascular hypertension and occurred in the pressure overloaded, hypertrophied left and in the norm otensive, nonhypertrophied right ventricle. The competitive aldosterone rec eptor antagonist, spironolactone, was able to prevent fibrosis in both vent ricles in either model of arterial hypertension irrespective of the develop ment of left ventricular hypertrophy and hypertension. To examine whether a ldosterone stimulates collagen synthesis in adult rat cardiac fibroblasts c ollagen synthesis, normalized per total protein synthesis, was measured by 3H-proline incorporation in cultured fibroblasts after 24 hours incubation with aldosterone at 10(-11) to 10(-6) M concentrations, or with 10(-9) M al dosterone + 10(-9) M spironolactone. Under serum-free conditions, aldostero ne was able to stimulate collagen synthesis in a dose-dependent manner and at concentrations (10(-9) M) which were comparable to stimulated states in vivo (e.g), renovascular hypertension, or chronic heart failure). At equimo lar concentrations, spironolactone abolished the aldosterone-mediated incre ase in collagen synthesis. Thus, in-vivo and in-vitro evidence could be provided that the mineralocort icoid, aldosterone, plays a pivotal role in promoting myocardial fibrosis a nd that could be antagonized by its competitive receptor blocker, spironola ctone. These cardioprotective effects of spironolactone may explain the pro gnostic value of anti-aldosterone therapy in patients with severe chronic h eart failure evaluated in the RALES mortality trial.